Inhibition of T-Type Voltage Sensitive Calcium Channel Reduces Load-Induced OA in Mice and Suppresses the Catabolic Effect of Bone Mechanical Stress on Chondrocytes
Date
2015-05-26
Journal Title
Journal ISSN
Volume Title
Publisher
PLOS (Public Library of Science)
Abstract
Voltage-sensitive calcium channels (VSCC) regulate cellular calcium influx, one of the earliest
responses to mechanical stimulation in osteoblasts. Here, we postulate that T-type
VSCCs play an essential role in bone mechanical response to load and participate in events
leading to the pathology of load-induced OA. Repetitive mechanical insult was used to induce
OA in Cav3.2 T-VSCC null and wild-type control mouse knees. Osteoblasts (MC3T3-
E1) and chondrocytes were treated with a selective T-VSCC inhibitor and subjected to fluid
shear stress to determine how blocking of T-VSCCs alters the expression profile of each
cell type upon mechanical stimulation. Conditioned-media (CM) obtained from static and
sheared MC3T3-E1 was used to assess the effect of osteoblast-derived factors on the
chondrocyte phenotype. T-VSCC null knees exhibited significantly lower focal articular cartilage
damage than age-matched controls. In vitro inhibition of T-VSCC significantly reduced
the expression of both early and late mechanoresponsive genes in osteoblasts but
had no effect on gene expression in chondrocytes. Furthermore, treatment of chondrocytes
with CM obtained from sheared osteoblasts induced expression of markers of hypertrophy
in chondrocytes and this was nearly abolished when osteoblasts were pre-treated with the
T-VSCC-specific inhibitor. These results indicate that T-VSCC plays a role in signaling
events associated with induction of OA and is essential to the release of osteoblast-derived
factors that promote an early OA phenotype in chondrocytes. Further, these findings suggest
that local inhibition of T-VSCC may serve as a therapy for blocking load-induced bone
formation that results in cartilage degeneration
Description
Publisher's PDF.
Keywords
Citation
Srinivasan PP, Parajuli A, Price C, Wang L, Duncan RL, Kirn-Safran CB (2015) Inhibition of TType Voltage Sensitive Calcium Channel Reduces Load-Induced OA in Mice and Suppresses the Catabolic Effect of Bone Mechanical Stress on Chondrocytes. PLoS ONE 10(5): e0127290. doi:10.1371/journal.pone.0127290